Angiopoietin‐Like Protein 4 Is a High‐Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type‐2 Diabetic Patients

Abstract

Background: ANGPTL 4 (angiopoietin‐like protein 4) is a LPL (lipoprotein lipase) inhibitor and is present in high‐density lipoprotein ( HDL ). However, it is not defined whether ANGPTL 4 in HDL s could affect HDL metabolism and function in type 2 diabetes mellitus (T2 DM ). Methods and Results: ANGPTL 4 levels in the circulation and HDL s were quantified in nondiabetic participants (n=201, 68.7% females) and T2 DM patients (n=185, 66.5% females). HDL s were isolated from nondiabetic controls and T2 DM patients to assess cholesterol efflux or subjected to endothelial lipase ( EL )‐overexpressed HEK 293 cells for EL hydrolysis in vitro. The association between ANGPTL 4 in HDL s and HDL components and function was analyzed in nondiabetic participants or diabetic patients, respectively. Plasma or HDL s of ANGPTL 4+/+ and ANGPTL 4−/− mice was subjected for cholesterol efflux or EL hydrolysis, respectively. ANGPTL 4 levels in the plasma and HDL s were 1.7‐ and 2.0‐fold higher in T2 DM patients than nondiabetic controls, respectively ( P <0.0001). Multivariable analysis demonstrated that per 1 doubling increase of ANGPTL 4 levels in HDL s, the changes amounted to +0.27% cholesterol efflux ( P =0.03), +0.06 μg/mL apolipoprotein A‐I ( P =0.09) and −9.41 μg/L serum amyloid A ( P =0.02) in nondiabetic controls. In T2 DM patients, the corresponding estimates were −0.06% cholesterol efflux ( P =0.10), −0.06 μg/mL apolipoprotein A‐I ( P =0.38), and +3.64 μg/L serum amyloid A ( P =0.72). HDL s isolated from ANGPTL 4−/− mice showed accelerated hydrolysis by EL and reduced cholesterol efflux compared with ANGPTL 4+/+ littermates. Conclusions: Physically, ANGPTL 4 in HDL s protected HDL s from hydrolysis. Resulting from increased circulating ANGPTL 4 levels in T2 DM , ANGPTL 4 levels in HDL s were elevated but with compromised inhibitory effect on EL , leading to increased HDL hydrolysis and dysfunction.